Dipyridamole, represented by structural formula (I), possesses platelet aggregation inhibiting, anti-thrombotic and vasodilator properties and it is marketed as an anti-platelet therapy for the treatment and prevention of disorders such as thrombo-embolisms.

A process for the preparation of dipyridamole, disclosed in U.S. Pat. No. 3,031,450, involves the reaction of 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine (see Scheme 1). The preparation of 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine is also reported in U.S. Pat. No. 3,031,450 and is incorporated herein by reference. The reaction to prepare dipyridamole does not employ an additional reaction solvent and is a neat mixture of the two reactants carried out at a very high temperature of 190 to 195° C. The process also involves a cumbersome work-up to isolate dipyridamole, since the crude product obtained is a pasty mass which needs decantation of the mother liquor and further purification. This decantation process is not practical on commercial scale.

A similar process for the production of dipyridamole is described in patent DD 117456 wherein the reaction conditions exemplified are heating 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine and diethanolamine at 155 to 160° C. under vacuum. However, this process again requires a high temperature which leads to the formation of impurities.
A process for the preparation and purification of dipyridamole is disclosed in patent DE 1812918, wherein 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine and diethanolamine are heated to 150 to 200° C. After completion of the reaction, the reaction mixture is dissolved in chloroform, which is further separated into an upper layer of diethanolamine and its hydrochloride and a chloroform solution. The chloroform solution obtained is separated and reduced to dryness after stirring with water. This process also requires a high temperature which can lead to the formation of impurities. In addition, the solvent used for the isolation of dipyridamole, chloroform, is inconvenient as it is a restricted solvent and its permitted limit in the final marketed dipyridamole is very low.
A similar process, wherein dipyridamole is manufactured by the reaction of diethanolamine with 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine is disclosed in patent RO 104718. However, this process again requires high temperatures of 180 to 200° C. which leads to the formation of impurities and, consequently, the yield of the final product is very low (58%) with a purity of less than 98%.
A process is disclosed in patent DD 115670, wherein the purification of dipyridamole involves refluxing it in butyl acetate, AcOBu, for 2 hours in the presence of an equal amount of silica gel or column chromatography on silica gel at 60-100° C. However, purification by column chromatography is not economical and not feasible on industrial scale. Moreover, this purification process only removes one specific impurity, 2,4,6-tris-(diethanolamino)-8-piperidino-pyrimido(5,4-d)pyrimidine.
The processes described above to prepare dipyridamole do not employ an additional reaction solvent but involve neat mixtures of the two reactants, 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine and diethanolamine, which are heated at very high temperatures. The use of neat reaction mixtures and/or high temperatures means that it is very difficult to control the levels of impurities formed.
Another process for the preparation of dipyridamole, disclosed in patent application WO 2007/080463, involves reacting diethanolamine with 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine in a solvent selected from the group consisting of 1-methyl-2-pyrrolidinone, sulpholane and polyethylene glycol. However, the exemplified reaction temperatures are very high at 190 to 200° C. and the HPLC purity of the crude dipyridamole is reported to be only 90-94%. A purification method is disclosed using first a ketonic solvent and then an alcohol and water. Even though the process disclosed in this patent application uses a solvent in the reaction, the temperature of reaction is still very high and the purification in ketonic solvent is reported at high temperature (100 to 120° C.). The HPLC purity after purification is reported as only 99.0-99.5%.
As discussed above, all the processes disclosed in the prior art for the preparation of dipyridamole suffer from serious disadvantages with respect to commercial production. The prior art synthetic and purification processes employ high temperatures in the preparation of dipyridamole which leads to inefficiency and high processing costs. The high temperatures also lead to higher levels of impurities being formed during manufacture with the consequence that further cumbersome and expensive purification procedures are required.
Considering the importance gained by dipyridamole as a commercial medicine, there is a great need for developing simple, inexpensive, good yielding and commercially feasible processes for the manufacture of high quality dipyridamole.